PROJECT SUMMARY/ABSTRACT This proposal is a five-year career development plan strategically formulated to train the candidate by way of mentoring, course-work and didactic activities, and hands-on conduct of research to become an independent investigator with a scientific focus on clinical outcomes related to fungal infections in cystic fibrosis (CF). The project will be carried out under the mentorship of Steven Kawut, MD, MS, a tenured Professor of Medicine and Epidemiology. He has a strong track record of successfully mentoring fellows and junior faculty and holds a K24 to support his mentoring activities. An advisory committee has been assembled to oversee the scientific progress, career development, and academic evolution of the candidate. The proposed research will investigate the risk factors for Aspergillus species (spp) isolation, the most common filamentous fungi observed in CF, and address the critical knowledge gaps regarding the independent impact of Aspergillus isolation on quality-of-life and treatment effects of antifungal therapies in individuals with CF. We plan to achieve this by focusing on three objectives. We will conduct a prospective cohort study of children and adults with CF from the Children's Hospital of Philadelphia (CHOP) and the University of Pennsylvania (Penn) and perform selective fungal culture and internal transcribed spacer (ITS) sequencing of respiratory samples. We aim to (1) identify modifiable risk factors for Aspergillus spp isolation in CF sputum and (2) determine the impact of Aspergillus spp isolation on respiratory related quality of life (measured by the Cystic Fibrosis Questionnaire-revised) and pulmonary exacerbations, adjusting for potential confounders, such as age, sex, pancreatic insufficiency, lung function, and co-infection. (3) In a retrospective multicenter cohort of CF patients in the United States, we will conduct a comparative effectiveness study of antifungal therapy compared to usual care (no antifungal therapy) on reducing pulmonary exacerbations utilizing propensity-score methods to account for potential cofounders, including age, sex, genotype, bacterial co-infection, and disease severity. Collectively, these three aims will provide insight to the factors contributing to development of Aspergillus spp in CF and elucidate the impact of Aspergillus spp on CF lung health. Furthermore, if we find a treatment effect of antifungal therapy, these data will serve as critical preliminary data to devise a clinical trial of targeted antifungal therapy in CF patients with Aspergillus.